Therapeutic strategies in radiation oncology based upon the use of radionuclides affixed to carriers have recently become the subject of considerable speculation and laboratory investigation. Although easily conceptualized, the successful targeting of radionuclides to tumor cells by specific carrier molecules and the subsequent deposition of lethal amounts of ionizing radiation remain an elusive goal. Simple stated, the difficulty lies in the scarcity of specific carrier molecules and radionuclides with appropriate decay characteristics. With thoughtful selection of radionuclides and carriers, however, physical and pharmacological manipulation in biological systems can be exploited to produce the desired therapeutic distribution and activity - e.g., receptor translocation of radiolabeled steroid hormones in human breast cancer cells and radiolabeled malanin precursors in malignant melonoma. Position specific, carrier-free 125I labeled estrogens and antiestrogens with high receptor affinity, prolonged nuclear retention time and low non-specific binding will be synthesized (eg, 3-iodo-3'-fluorodiethylstilbestrol, 17Alpha-iodovinyl-4-fluoroestradiol and 17Alpha-iodo-11Beta-methoxyestradiol). Receptor affinity constants will be determined and cytotoxicity measured in cultured human breast cancer cells. The chemical and biological variables which regulate, limit or enhance specific cell killing will be investigated. Chromosomal aberrations induced by 125I hormones will be compared to those induced by the thymidine analogue 125IUdR. Carrier-free 125I and 211At labeled melanin precursors which show high selectivity for melanoma cells in vitro and in vivo will be synthesized (eg, 5,6-dihydroxyindole, 5-thiouracil and difluoromethyl ornithine). These compounds will be evaluated in melanotic and amelanotic cell lines and experimental tumor systems. This proposal aims to answer general quantitative questions about the potential use of Auger and alpha emitters for radiation therapy. The research has significance at two levels - in the field of oncology, the emphasis is on the possibility of using the radiotoxicity of Auger and alpha emitters for cancer treatment; in the field of cellular and molecular radiation biology, the emphasis is on the mechanism of action of alpha particles and the Auger effect.